Patent Application
20070032694
The invention relates to stents with a radioactive surface coating, processes for their production and their use for restenosis prophylaxis.
Radioactive stents are prior art (EP 0433011, WO 94/26205, U.S. Pat. No. 5,176,617). Stents are endoprostheses that make it possible to keep open duct-like structures in the bodies of humans or animals (e.g., vascular, esophageal, tracheal and bile duct stents). They are used as palliative measures in the case of stenoses by obstruction (e.g., arteriosclerosis) or external pressure (e.g., in the case of tumors). Radioactive stents are used, for example, after vascular-surgery interventions or radiological interventions (e.g., balloon angioplasty) for restenosis prophylaxis. Such radioactive stents can be produced, for example, by activation of a non-radioactive stent using irradiation with protons or deuterons from a cyclotron (WO 94/26205). This process for the production of radioactive stents is named ion implantation.
There is now the problem that, on the one hand, generally no cyclotron is available at the site of the use of the stent to undertake an activation of the stent, and, on the other hand, the activated stent cannot be stored indefinitely or transported in any arbitrary way due to the sometimes short half-life of the activated isotope and for reasons of protection against radiation.
The object of this invention is therefore to make available stents and new processes for their production, and said stents can be activated independently by a cyclotron. In particular, the object of the invention is to make available stents that can be coated independently by a cyclotron with a preselected radioactive isotope.
This object is achieved by the stents that are described below and the processes for their production, as they are characterized in the claims.
The above-described object is achieved by the production processes for radioactive stents that are described below. In contrast to ion implantation, the processes according to the invention for the production of radioactive stents are based on chemical or electrochemical methods.
Within the framework of this application, the notations nnX and X-nn (X: element symbol, nn: mass number) are to be regarded as synonymous for radioactive isotopes (Example: 110Ag corresponds to Ag-110).
The above-described object is achieved in a first variant by a process for the production of a radioactive stent, in which a chemical deposition of the radioactive isotope is carried out on the stent.
To this end, the selected stent is immersed in a solution that contains the radioactive isotope. The radioactive isotope is then chemically deposited on the stent. Depending on the selected material of the stent, on the one hand, and the radioactive isotope that is to be deposited, on the other hand, two possible types of deposition are considered:
1) Chemical Reduction
During chemical reduction, a reducing agent (e.g., SnCl2, KBH4, dimethylborane, formaldehyde, sodium hypophosphite) is added to the solution that contains the radioactive isotope in dissolved form as well as the stent.
Survey:
M2++2e− (from the reducing agent)→catalytic surface→M0
Reducing Agent Hypophosphite (with Ni)
H2PO2−+H2O→catalytic surface→HPO32−+2H++H−
2H−+Ni2+→Ni H2
Reducing Agent NaBH4 (with Au, Ni)
BH4−+H2O→BH3OH−+H2
BH3OH−+3Au(CN)2−+3OH−→catalytic surface→BO2−+1.5H2+3 Au0+6CN−+2H2O
2Ni2++NaBH4+2H2O→catalytic surface→2Ni0+2H2+4H++NaBO2
Reducing Agent Formaldehyde: (with Cu)
Cu2++2 HCOH+4OH−→catalytic surface→Cu0+H2+2H2O+2HCOO−
Reducing Agent Hydrazine: (with Pd, Pt)
Reducing Agent Dimethylaminoborane (CH3)2NH—BH3 (with Au, Ag)
(CH3)2NH—BH3+OH—→catalytic surface→BH3OH−+(CH3)2NH
After 1 minute to 10 hours, the stent is removed from the respective solution and washed. The stent is coated on the surface with the radioactive isotope.
In this way, for example, radioisotopes of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal stents (e.g., steel, nitinol).
2) Chemical Precipitation
During chemical precipitation, a precipitating agent (e.g., oxalic acid, phosphoric acid or salts thereof or Na2CO3) is added to the solution that contains the radioactive isotope in dissolved form as well as the stent.
In this way, for example, radioisotopes of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal stents (e.g., steel, nitinol).
The above-described object is achieved in a second variant, in that the radioactive isotope is secured by means of an adhesive to the surface of the stent.
The device according to the invention thus consists of the metal parent substance of the stent, an adhesive on the surface of the stent and an adhesive radioactive isotope.
As a parent substance, the commercially available vascular implants can be used, e.g., a Wiktor stent, a Strecker stent or a Palmaz-Schatz stent.
As adhesives, peptides, fats or gold in combination with a thiol-group-containing complexing agent are used.
It is thus possible, for example, to use modified polyurethanes that in turn contain complexing agents.
As adhesives, however, peptides can also be used that on the one hand carry a complexing agent and on the other hand bind specifically to the metal of the stent. Examples of these compounds are labeled endothelin derivatives, as they are described in, e.g., EP 606683, DE 4425778, DE 43 37 600, DE 4337599 and DE 19652374 (e.g., Tc-99m-Asp-Gly-Gly-Cys-Gly-Cys-Phe-(Dr-Trp)-Leu-Asp-Ile-Ile-Trp).
As adhesives, fats that carry a complexing agent can also be used. Examples of this are the complexing agents that carry lipophilic radicals and that are mentioned in DE 43 40 809, EP 450742, EP 438206, EP 413405 or WO 96/26182.
Moreover, gold in combination with a thiol-group-containing complexing agent can also be used as an adhesive. It is known that thiol-group-containing compounds show an increased affinity to gold-coated surfaces (H. Schönherr et al. J. Am. Chem. Soc. 118 (1996), 13051-13057). Surprisingly enough, elementary gold that is on the surface of the stent is also able to secure specific complexing agents, if they have thiol groups. The complexing agents in turn secure the radioactive isotopes.
For the purposes of this document, complexing agents are, e.g., DTPA, DOTA, DO3A, EDTA, TTHA, MAG2-amides, MAG3-amides and derivatives thereof.
As radioactive isotopes, the radioactive isotopes of elements Ag, Au, Ba, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, S, Sb, Sc, Sm, Tb, Tc or Y can be used.
The invention therefore relates to radioactive stents, characterized in that the radioactive isotope is secured to the surface of the stent by means of an adhesive.
The stents according to the invention can be produced as follows by way of example:
A. Peptide as an Adhesive
B. Fat as an Adhesive
C. Gold/Thiol-Group-Containing Complexing Agents as Adhesives
The above-described processes are generally performed at temperatures of 0-100° C. In the coating of the stent with the adhesive, solvents can be used on the basis of the respective adhesive. When a non-aqueous solvent is used, the latter is to be removed before the implantation.
The stents can also be coated with two or more different isotopes. It is possible in particular to apply short-lived or long-lived isotopes together on a stent (for example, 55Co with 55Fe, 35S with 67Cu or 99Mo with 57Co).
The operations that are necessary for implementing the above process that is described in principle are known to one skilled in the art. Special embodiments are described in detail in the examples.
In a third variant, the invention also relates to a process for the production of radioactive stents, which is characterized in that a non-radioactive stent is immersed in a solution that contains at least one radioactive isotope in ionic form, and the isotope is then chemically deposited on the stent.
The above-described object is achieved according to the invention by an electrochemical deposition of the radioactive metal isotope on the stent.
To this end, the selected stent is immersed in a solution that contains the radioactive metal isotope. The radioactive isotope is then electrochemically deposited. On the basis of the selected materials of the stent, on the one hand, and the radioactive isotope that is to be deposited, on the other hand, two possible types of deposition are considered:
For the coating of metal stents, two electrochemical processes have proven especially suitable: electroplating (electrolytic coating) and cementation (internal electrolysis). The process with the broader range of application is the electroplating, since it also makes possible the coating with an electrochemically more negative material than that of the stent. The coating also makes possible chemical reactions—for example reductive processes.
From the user-friendly operation, it can be seen that the cementation is the better process: the stent is added to the solution of an electrochemically more positive element, and the coating is carried out without a parasitic current.
By suitable cell shape, the excess coating material can be kept small. The necessary stirring can be done by a magnetic stirrer or by moving the stent manually. Since only small amounts of substance are applied in this process, manual stirring is reasonable. The same also holds true for reactions at elevated temperature: because of the short time available, thermostating is not necessary; preheating is all that is required.
The coating of cells (
In the cells that are described in
The use of the stent with its carrier has the advantage that the inside of the stent is shielded, and thus no coating is carried out there. The coating is carried out only at the locations that are directed against the vessel.
Since a restenosis is suppressed by the coating, an electropolishing of the crude stent may be omitted—especially in the case of high-grade steel.
Possible Types of Electrochemical Labeling of Stents:
Galvanostatic Deposition
For this purpose, a battery (1.5-12 V) that is connected with a variable resistor and 2 electrode terminals is sufficient. The metal that is to be coated is connected as a cathode. As an anode, a noble metal, preferably platinum, should be used. The electrolysis period is 20 seconds to 30 minutes. The operation is performed at temperatures of 0°-80° C., but preferably at room temperature.
Cu: (e.g., Cu-67, β and γ Str., t1/2=61.9 h) from pyrophosphate baths of the composition below:
Au: (Au-199, t1/2=3 d, β and γ Str.)
In: from cyanidic baths at pH=0-1
Re: from perrhenate Re-186
Ni: from NiSO4/boric acid or from acetate, fluoroborate or sulfamate baths,
Pt, Rh, Pd, Ru:
Ag: (Ag-110, t1/2=250 d)
The labeling of the stent is done by electrochemical deposition of radioactive metal corresponding to its electrochemical potential in terms of the potential of the stent metal. The deposition is performed in a suitable electrolyte and under selected reaction conditions. An especially suitable electrolyte is hydrochloric acid at the concentrations of 0.75N and 1N. In this way, all radioisotopes of metals, whose electrochemical potential is more positive than that of the stent metal, can be deposited.
It has been shown that after the electrochemical deposition of the radioactive metal, nonspecifically-bonded activity still adheres to the stent to some extent. To remove the latter, the stent is treated with a solution that contains an electrolyte (e.g., NaCl), a reducing agent and a hydroxycarboxylic acid (e.g., SnCl2 and gentisic acid) or an alcohol and lipophilic cations (e.g., alcoholic tetrabutylammonium bromide solution).
Then, the thus produced stent can still be sealed with a polymer. As a polymer, e.g., a polyacrylate is suitable.
All stents can also be coated with two or more different isotopes. In particular, it is possible to apply short-lived and long-lived isotopes together on a stent (for example, 55Co with 55Fe or 99Mo with 57Co).
With the described process, it is possible to produce radioactive stents that contain on the surface at least one radioisotope of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y.
The invention therefore relates to such stents, as well as the processes for their production. The operations that are necessary for implementing the above processes that are described in principle are known to one skilled in the art. Special embodiments are described in detail in the examples.
The stents according to the invention achieve the above-described object. Stents can be radiolabled easily by the disclosed processes and metered precisely. The stents according to the invention are readily physiologically compatible. As it was possible to show in the animal model, the restenosis is significantly inhibited after balloon denudation by implantation of the stent according to the invention.
The special advantage of the stent according to the invention is that the physician can select on the spot a (non-radioactive) stent according to his needs and can then activate the selected stent by the described process. The few substances and solutions that are required for this purpose can be supplied prepared accordingly, so that the corresponding physician need only immerse the uncoated stent in the individual solutions in the specific sequence. The invention thus also relates to those substances, solutions and preparations (kits) that are prepared for the processes according to the invention.
The following examples are to explain the subject of the invention, without intending that it be limited to these examples.
A Wiktor stent (22.85 mg, model 6570, Medtronic) is covered with a layer of 2 ml of saturated sodium oxalate solution. 37 MBq of yttrium-90-trichloride solution is added and heated for 30 minutes to 60° C. Then, the stent is removed and washed three times with 5 ml of 0.9% sodium chloride solution. The thus labeled Wiktor stent carries an activity of 0.88 MBq of Y-90.
A strecker stent (6.51 mg, SS/5-4, Boston Scientific) is covered with a layer of 726 μl of sodium pertechnetate solution (231.9 MBq). 100 μl of tin(II)-chloride dihydrate solution (5 mg of SnCl.2H2O/1 ml of 0.01 M HCl) is added, the reaction mixture is put into an ultrasound bath for 5 minutes and finally incubated for 25 minutes at room temperature. The stent is dried and washed three times for 15 minutes with 726 μl of 0.9% sodium chloride solution. Finally, it is again covered with a layer of 726 μl of 0.9% sodium chloride solution, and the reaction mixture is put into an ultrasound bath for 5 minutes. The dried Strecker stent caries an activity of 1.1 MBq-Tc-99m/6.51 mg (≅29.7 μCi/6.51 mg≅4.6 μCi/1 mg).
A Strecker stent (6.60 mg, SS/5-4, Boston Scientific) is covered with a layer of 736 μl of sodium perrhenate solution (240.2 MBq). 100 μl of tin(II)-chloride-dihydrate solution (5 mg of SnCl2.2H2O/1 ml of 0.01 M HCl) is added, the reaction mixture is put into an ultrasound bath for 5 minutes and finally incubated for 25 minutes at room temperature. The stent is dried and washed three times for 15 minutes with 736 μl of 0.9% sodium chloride solution. Finally, it is again covered with a layer of 736 μl of 0.9% sodium chloride solution, and the reaction mixture is put into an ultrasound bath for 5 minutes. The dried Strecker stent carries an activity of 1.0 MBq-Re-186/6.6 mg (≅27 μCi/6.6 mg≅4.1 μCi/1 mg).
A Wiktor stent (22.92 mg, model 6570, Medtronic) is covered with a layer of 2.56 ml of sodium pertechnetate solution (911.5 MBq). 256 μl of tin(II)-chloride-dihydrate solution (5 mg of SnCl2.2H2O/1 ml of 0.01 M HCl) is added, the reaction mixture is put into an ultrasound bath for 5 minutes and then incubated for 25 minutes at room temperature. The stent is dried and washed three times for 15 minutes with 2.56 ml of 0.9% sodium chloride solution. Finally, it is again covered with a layer of 2.56 ml of 0.9% sodium chloride solution, and the reaction mixture is put into an ultrasound bath for 5 minutes. The dried Wiktor stent carries an activity of 5.9 MBq-Tc-99m/22.92 mg (≅159.5 μCi/22.92 mg≅6.9 μμCi/1 mg).
A Wiktor stent (22.31 mg, model 6570, Medtronic) is covered with a layer of 2.5 ml of sodium perrhenate solution (884.1 MBq). 249 μl of tin(II) chloride dihydrate solution (5 mg of SnCl2.2H2O/1 ml of 0.01 M HCl) is added, the reaction mixture is put into an ultrasound bath for 5 minutes and finally incubated for 25 minutes at room temperature. The stent is dried and washed three times for 15 minutes with 2.5 ml of 0.9% sodium chloride solution. Finally, it is again covered with a layer of 2.5 ml of 0.9% sodium chloride solution, and the reaction mixture is put into an ultrasound bath for 5 minutes. The dried Wiktor stent carries an activity of 5.2 MBq-Re-186/22.31 mg (≅140.5 μCi/22.31 mg≅6.3 μCi/1 mg).
The Wiktor stent (model 6570, Medtronic) was coated with Tc-99m as described in Example 4. In an anesthetized (Rompun/Ketavet 1:2) white New Zealand rabbit (3.2 kg of body weight), the femoral artery was exposed. The labeled Wiktor stent was inserted into the vessel via a 5 F sluice and secured in the infrarenal aorta by inflating the balloon catheter. The catheter was then removed, and both the femoral artery and the wound were sutured. Over a period of 8 hours after administration of the stent, whole-body scintigrams were prepared with the aid of a commercially available gamma camera. Five hours after administration of the stent, a scintigram was prepared. Activity could only be located in the area of the stent that is in the infrarenal aorta of the animal. During the entire examination period, no detectable activity was rinsed from the stent. After 8 hours, the rabbit was killed, the stent was removed, and the activity was measured in the gamma counter. The activity that adheres to the stent was equally as high as at the beginning of the test, taking into consideration the radioactive decomposition of 99mT into 99Tc.
A Strecker stent (1993 mg) in an alkaline copper sulfate/potassium-sodium tartrate solution with an activity of 47.3 MBq is added to a cementation cell (
A nitinol stent (496 mg) in a solution that consists of potassium-gold cyanide (K[99Au(CN)4]) with an activity of 137.8 MBq, potassium cyanide and potassium hydroxide is added to a cementation cell (
A Strecker stent (997 mg) in a solution that consists of sodium-silver cyanide (NaAg(CN)2) with an activity of 40 MBq/mg of stent, sodium cyanide, sodium hydroxide and is added to a cementation cell. After being heated to 55° C., dimethylborane is added. It is stirred for 4 minutes at 55° C., then the solution is drained off, the stent is washed four times with physiological common salt solution, and the activity is determined. It is 1.34 MBq.
Na[Ag(CN)2]: 134 mg of AgCN + 49 mg of NaCN
A Strecker stent (1996 mg) in a solution that consists of palladium chloride, hydrochloric acid, ammonia and ammonium chloride is added to a cementation cell (
3 g of hypophosphite yields 1 g of Pd alloy with 1.5% P
A high-grade steel stent (498 mg) in a solution that consists of palladium chloride, hydrochloric acid, ammonia and ammonium chloride is added to a cementation cell (
3 g of hypophosphite yields 1 g of Pd alloy with 1.5% P
A nitinol stent (96 mg) in a solution that consists of palladium chloride, hydrochloric acid, ammonia and ammonium chloride is brought into a cementation cell (
3 g of hypophosphite yields 1 g of Pd-alloy with 1.5% P
A high-grade steel stent (1992 mg) in a solution of phosphoric acid that is heated to 50° C. with a 32P activity of 41.4 MBq is brought into a galvanization cell (
50 mg of 1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 43 40 809.5) is dissolved in 1 ml of ethanol. The Wiktor stent (22.82 mg, model 6570, Medtronic) is covered with a layer of the solution that is thus produced. Then, 2 ml of water is added and incubated for 15 minutes in an ultrasound bath. The Wiktor stent is removed and dried.
A Wiktor stent that is coated as under Example 14a with 1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 43 40 809.5) is covered with a layer of 2 ml of 0.9% sodium chloride solution. After 37 MBq of indium-trichloride solution is added, the reaction mixture is put into an ultrasound bath for 15 minutes. The stent is removed, the latter is washed three times with 5 ml of 0.9% sodium chloride solution and dried. The Wiktor stent that is thus labeled carries an activity of 1.49 MBq of In-111.
A Wiktor stent that is coated with 1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 43 40 809.5) as under Example 14a is covered with a layer of 2 ml of 0.9% sodium chloride solution. After 37 MBq of yttrium-90-trichloride solution is added, the reaction mixture is put into an ultrasound bath for 15 minutes. The stent is removed, the latter is washed three times with 5 ml of 0.9% sodium chloride solution and dried. The Wiktor stent that is thus labeled carries an activity of 1.12 MBq of Y-90.
50 mg of 1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 4340809.5) is dissolved in 1 ml of ethanol. After 37 MBq of yttrium-90-trichloride solution is added, the reaction mixture is refluxed for 10 minutes. The Y-90 complex solution that is thus prepared can be used without further purification for coating a Wiktor stent.
A Wiktor stent (22.89 mg, model 6570, Medtronic) is added to 900 μl of the solution, produced under Example 15a, of 1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-Y-90-complex. After 2 ml of water is added, the reaction mixture is put into an ultrasound bath for 15 minutes. Then, the Wiktor stent is removed and washed three times with 5 ml of 0.9% sodium chloride solution. The Wiktor stent that is thus labeled carries an activity of 0.98 MBq of Y-90.
3.57 g (10 mmol) of diethylene-triamine-pentaacetic acid-bisanhydride is suspended together with 4.05 g (40 mmol) of triethylamine in 100 ml of absolute dimethylformamide. Then, a solution of 3.42 g (20 mmol) of undecylamine, dissolved in 50 ml of absolute dichloromethane, is added in drops to the reaction mixture at room temperature. The reaction batch is stirred for 6 hours at room temperature, filtered and concentrated by evaporation in a medium-high vacuum. The residue is dissolved three times in 100 ml of dimethylformamide and in each case concentrated by evaporation in a medium-high vacuum. 50 ml of absolute diethyl ether is poured over the foamy reaction product and stirred overnight. It is filtered and dried in a medium-high vacuum.
50 mg of N,N′-bisundecyl-diethylene-triamine-pentaacetic acid-diamide (produced according to Example 16a) is dissolved in 1 ml of ethanol. The Wiktor stent (22.93 mg, model 6570, Medtronic) is covered with a layer of the solution that is thus produced. Then, 2 ml of water is added, and it is incubated for 15 minutes in an ultrasound bath. The Wiktor stent is removed and dried.
A Wiktor stent that is coated with N,N′-bisundecyl-diethylene-triamine-pentaacetic acid-diamide as under Example 16b is covered with a layer of 2 ml of 0.9% sodium chloride solution. After 37 MBq of indium-trichloride solution is added, the reaction mixture is put into an ultrasound bath for 15 minutes. The stent is removed, the latter is washed three times with 5 ml of 0.9% sodium chloride solution and dried. The Wiktor stent that is thus labeled carries an activity of 1.34 MBq of In-111.
A Wiktor stent that is coated with N,N′-bisundecyl-diethylene-triamine-pentaacetic acid-diamide as under Example 16b is covered with a layer of 2 ml of 0.9% sodium chloride solution. After 37 MBq of yttrium-trichloride solution is added, the reaction mixture is put into an ultrasound bath for 15 minutes. The stent is removed, the latter is washed three times with 5 ml of 0.9% sodium chloride solution and dried. The Wiktor stent that is thus labeled carries an activity of 1.11 MBq of Y-90.
50 mg of N,N′-bisundecyl-diethylene-triamine-pentaacetic acid-diamide (Example 4a) is dissolved in 1 ml of ethanol. After 37 MBq of yttrium-90-trichloride solution is added, the reaction mixture is heated for 10 minutes to 60° C. The Y-90-complex solution that is thus prepared can be used without further purification for coating a Wiktor stent.
A Wiktor stent (22.87 mg, model 6570, Medtronic) is added to 900 μl of the solution, produced under Example 17a, of the Y-90 complex of N,N′-bisundecyl-diethylene-triamine-pentaacetic acid-diamide. After 2 ml of water is added, the reaction mixture is put into an ultrasound bath for 15 minutes. Then, the Wiktor stent is removed and washed three times with 5 ml of 0.9% sodium chloride solution. The Wiktor stent that is thus labeled carries an activity of 0.99 MBq of Y-90.
3.63 g (10 mmol) of N-benzyloxycarbonyl-glycyl-glycine-N-hydroxysuccinimide ester and 1.71 g (10 mmol) of undecylamine are dissolved in 100 ml of absolute dichloromethane. The reaction mixture is stirred for 6 hours at room temperature. Then, it is diluted with 100 ml of dichloromethane, the organic phase is washed twice with 50 ml of saturated sodium bicarbonate solution and once with 50 ml of water. It is dried on magnesium sulfate, and the solvent is evaporated in a vacuum. The crude product is purified by chromatography on silica gel (eluant: dichloromethane/methanol 95:5).
3 g (7.15 mmol) of N-benzyloxycarbonyl-glycyl-N′-undecyl-glycinamide (Example 18a) is dissolved in 100 ml of absolute ethanol. After 300 mg of palladium is added to carbon (10%), it is hydrogenated for 2 hours at room temperature (1 atmosphere of hydrogen). It is filtered and concentrated by evaporation in a vacuum. The resulting amine is used without further purification for the subsequent reaction.
285.4 mg (1 mmol) of glycyl-N′-undecyl-glycinamide (Example 18b) and 231.2 mg (1 mmol) of S-acetyl-mercapto-acetic acid-N-hydroxy-succinimide ester are dissolved together in 20 ml of absolute dichloromethane. The reaction mixture is stirred for 6 hours at room temperature. Then, it is diluted with 20 ml of dichloromethane, the organic phase is washed twice with 5 ml of semisaturated sodium bicarbonate solution and washed once with 5 ml of water. It is dried on magnesium sulfate, and the solvent is evaporated in a vacuum. The crude product is purified by chromatography on silica gel (eluant: dichloromethane/methanol 93:7).
201 mg (0.5 mmol) of N-(S-acetyl-mercaptoacetyl-glycyl-N′-undecyl-glycinamide (Example 18c) is dissolved in 15 ml of absolute ethanol. It is saturated with argon, and an ammonia stream is directed through the solution for 30 minutes. Then, it is concentrated by evaporation, and the residue is taken up in 20 ml of dichloromethane. The organic phase is shaken once with 2% aqueous citric acid and dried on sodium sulfate. The solvent is evaporated in a vacuum, and the residue is chromatographed on silica gel (eluant: dichloromethane/methanol 9:1).
50 mg of N-(mercaptoacetyl)-glycyl-N′-undecyl-glycinamide (Example 18d) is dissolved in 1 ml of ethanol. The Wiktor stent (22.89 mg, model 6570, Medtronic) is covered with a layer of the solution that is thus produced. Then, 2 ml of water is added, and it is incubated for 15 minutes in an ultrasound bath. The Wiktor stent is removed and dried.
A Wiktor stent that is coated with N-(mercaptoacetyl)-glycyl-N′-undecyl-glycinamide, as under Example 18e, is covered with a layer of 2 ml of disodium hydrogen phosphate buffer (0.1M, pH=8.5). After 37 MBq of perrhenate solution is added, 100 μl of tin dichloride-dihydrate solution (5 mg of SnCl2×2H2O/1 ml of 0.1M HCl) is added to the reaction batch. The reaction mixture is put into an ultrasound bath for 15 minutes. The stent is removed, the latter is washed three times with 5 ml of 0.9% sodium chloride solution and dried. The Wiktor stent that is thus labeled carries an activity of 1.31 MBq of Re-186.
5 mg of N-(mercaptoacetyl)-glycyl-N′-undecyl-glycinamide (Example 18d) is dissolved in 800 μl of ethanol. After 5 mg of disodium-L-tartrate and 50 μl of 0.1M sodium hydrogen phosphate buffer (pH=8.5) are added, 37 MBq of perrhenate and 100 μl of tin dichloride-dihydrate solution (5 mg of SnCl2×2H2O/1 ml of 0.1M HCl) are added. The reaction mixture is heated for 5 minutes to 60° C. The solution of the Re-186 complex of N-(mercaptoacetyl)-glycyl-N′-undecyl-glycinamide that is thus prepared can be used directly for labeling a Wiktor stent.
A Wiktor stent (22.99 mg, model 6570, Medtronic) is added to 900 μl of the solution, produced under Example 18g, of the Re-186 complex of N-(mercaptoacetyl)-glycyl-N′-undecyl-glycinamide. After 2 ml of water is added, the reaction mixture is put into an ultrasound bath for 15 minutes. Then, the Wiktor stent is removed and washed three times with 5 ml of 0.9% sodium chloride solution. The Wiktor stent that is thus labeled carries an activity of 1.13 MBq of Re-186.
A Wiktor stent (22.85 mg, model 6570, Medtronic) is covered with a layer of 2 ml of saturated sodium oxalate solution. 37 MBq of yttrium-90-trichloride solution is added and heated for 30 minutes to 60° C. Then, the stent is removed and washed three times with 5 ml of 0.9% sodium chloride solution. The Wiktor stent that is thus labeled carries an activity of 0.88 MBq of Y-90.
17.5 g of decanoic acid methyl ester is dissolved in 1 l of absolute ethanol and mixed with 350 ml of hydrazine hydrate. It is refluxed for 3 hours and then stirred overnight at room temperature. The solution is concentrated by evaporation to about 300 ml and allowed to stand until the product is crystallized out. After it is filtered off and dried, 16.6 g (=94% of theory) of decanoic acid hydrazide is obtained.
3.6 g of diethylenetriamine-pentaacetic acid-bisanhydride is dissolved in 500 ml of DMF and mixed under nitrogen atmosphere with 4.2 ml of triethylamine and 3.7 g of decanoic acid hydrazide. It is stirred for 24 hours at room temperature and then undissolved components are filtered off. The solution is concentrated by evaporation, and the oily residue is taken up in 500 ml of ether. After 500 ml of hexane is added and stirring is continued, the product precipitates in crystalline form. After drying, 7.2 g (=95% of theory) of bisdecyloylhydrazino-diethylene-triamine-pentaacetate is obtained.
2 mg of bisdecyloylhydrazino-diethylenetriamine-pentaacetate is dissolved in 1 ml of methanol and precipitated with the addition of 2 ml of hexane. In this suspension, a Strecker stent 0.5 cm in length (SS/5-4, Boston Scientific) is immersed and incubated for 15 minutes by means of ultrasound. The stent is then taken out and dried. This process is repeated five times, and finally excess coating material is removed by washing with physiological common salt solution in an ultrasound bath.
The thus treated stent was immersed for labeling in a commercially acquired solution of the radioactive metal isotope (In-111, Y-90, 74 MBq each) and incubated for 15 minutes in an ultrasound bath. Finally, it was washed in physiological saline for 20 minutes in an ultrasound bath. 0.3 MBq of residual activity remains on the stent.
2 mg of bisdecyloylhydrazino-diethylenetriamine-pentaacetate is dissolved in 1 ml of methanol and labeled with a commercially acquired solution of the radioactive metal isotope (In-111, Y-90, 74 MBq each). In this solution, a Strecker stent 0.5 cm in length (SS/5-4, Boston Scientific) is immersed and incubated for 15 minutes by means of ultrasound. Then, the stent was taken out and dried. This process was repeated 5 times, and finally soluble activity was removed by washing with physiological common salt solution in an ultrasound bath. 0.1 MBq of residual activity remains on the stent.
Production of Thioacetyl-Gly-Gly-amidoethyl-PEG-methylether
50 g of aminoethyl-polyethyleneglycol-methylether with a molecular weight of about 5000 is stirred with 3.6 g of N-benzyloxycarbonyl-glycylglycine-N-hydroxysuccinimide ester (Z-Gly-Gly-OSu) in 100 ml of DMF for 24 hours at room temperature. The solution is concentrated by evaporation, and the residue is further reacted without further purification.
The residue is dissolved in a mixture of methanol/water 1:1, mixed with 2 g of palladium on activated carbon and hydrogenated under hydrogen atmosphere (pressure 1 bar) until about 230 ml of hydrogen is taken up. Then, the catalyst is filtered off, and the remaining mixture is purified after concentration by evaporation with a gel filtration. After drying, 49 g (=96% of theory) of glycyl-glycyl-amidoethyl-PEG-methylether is obtained.
This product is dissolved in 100 ml of DMF and stirred with 2.2 g of S-acetyl-thioglycolic acid-N-hydroxysuccinimide ester for 24 hours at room temperature. Then, the mixture is mixed with 20 ml of aqueous ammonia solution and stirred for 2 more hours. The product is acidified to pH 4 with aqueous 6N hydrochloric acid and concentrated by evaporation. The purification is carried out on a gel filtration column. 42 g (=85% of theory) of thioacetyl-glycyl-glycyl-amidoethyl-polyethyleneglycol-methyl ester is obtained.
2 mg of thioacetyl-Gly-Gly-amidoethyl-PEG-methylether with a molecular weight of about 5300 was dissolved in 2 ml of methanol, precipitated with the addition of 1 ml of hexane, a Strecker stent 0.5 cm in length (SS/5-4, Boston Scientific) was immersed in this suspension and incubated by means of ultrasound for 15 minutes. Then, the stent was taken out and dried. This process was repeated five times, and finally excess coating material was removed by washing with physiological common salt solution in an ultrasound bath.
The thus treated stent was immersed for labeling in a solution of the radioactive metal isotope (Tc-99m, Re-186) that consists of 5 ml of the solution (Tc-99m from the generator, Re-186 that was acquired commercially and contained about 3 MBq of activity), 200 μl of phosphate buffer (Na2HPO4, 0.5 mol/l, pH 8.5), 50 μl of a 0.15 molar disodium tartrate solution and 2.5 μl of a 0.2 molar SnCl2 solution and incubated for 15 minutes in an ultrasound bath. Finally, it was washed in physiological saline for 20 minutes in an ultrasound bath. 0.1 MBq of residual activity remains on the stent.
0.5 mg of thioacetyl-Gly-Gly-amidoethyl-PEG-methylether with a molecular weight of about 5300 was dissolved in 300 μl of phosphate buffer (Na2HPO4, 0.5 mol/l, pH 8.5), and 50 μl of a 0.15 molar disodium tartrate solution and 2.5 μl of a 0.2 molar SnCl2 solution were added. The mixture was mixed with a pertechnetate solution (2 MBq) from a Tc-99m generator and incubated for 15 minutes at 60° C. A solution of polyethylene glycols that are labeled with Re-186 could be produced analogously.
A Strecker stent 0.5 cm in length (SS/5-4, Boston Scientific) was immersed in this solution and incubated for 15 minutes by means of ultrasound. Then, the stent was taken out and dried. This process was repeated several times in succession, until the adhering activity had reached 0.3 MBq. Then, it was washed twice for 60 minutes in physiological saline. A residual activity of 100 KBq remained.
0.5 mg of the Asp-Gly-Gly-Cys-Gly-Cys-Phe-(D-Trp)-Leu-Asp-Ile-Ile-Trp that was produced analogously to Barany and Marrifield, The Peptides; Analysis, Biology, Academic Press, New York, 1990; Stewart and Young, Solid-Phase Peptide Synthesis, 2nd Edition, Pierce Chemical Co., Rockford, Ill., 1984 is dissolved in 300 ml of phosphate buffer (Na2HPO4, 0.5 mol/l, pH 8.5) and mixed with 50 μl of a 0.15 molar disodium-L-tartrate solution, 2.5 μl, of a 0.2 molar tin(II) chloride-dihydrate solution. The reaction mixture is mixed with a pertechnetate solution (50 mCi=1.85 GBq) from an Mo-99/Tc-99m-generator and incubated for 10 minutes at room temperature.
A Strecker stent 0.5 cm in length (SS/5-4, Boston Scientific) was incubated five times in succession for 15 minutes each in the Tc-99m-peptide solution. After each incubation, the activity that adheres to the stent was determined with the aid of a commercially available gamma counter. As the figure shows, an activity of 230 μCi on the Strecker stent remained even after one-time incubation.
The repetitions of this incubation do not result in any significantly higher activity that remains on the stent. The stent that was coated with the Tc-99m-peptide solution was then washed four times every minute and twice for 60 minutes in physiological saline. After the first rinsing, 81 μCi still remains on the stent. The additional rinsing processes did not result in any significant reduction of the activity that is bonded to the stent.
A Wiktor stent (22.92 mg, model 6570, Medtronic) is covered with a layer of 2.56 ml of sodium-pertechnetate solution (911.5 MBq). 256 μl of tin(II) chloride-dihydrate solution (5 mg of SnCl2.2H2O/1 ml of 0.01 M HCl) is added, the reaction mixture is put into an ultrasound bath for 5 minutes and finally incubated for 25 minutes at room temperature. The stent is dried and washed three times for 15 minutes with 2.56 ml of 0.9% sodium chloride solution. Finally, it is again covered with a layer of 2.56 ml of 0.9% sodium chloride solution, and the reaction mixture is put into an ultrasound bath for 5 minutes. The dried Wiktor stent carries an activity of 5.9 MBq-Tc-99m/22.92 mg (≅159.5 μCi/22.92 mg≅6.9 μCi/1 mg).
A Wiktor stent (22.31 mg, model 6570, Medtronic) is covered with a layer of 2.5 ml of sodium pertechnetate solution (884.1 MBq). 249 μl of tin(II) chloride-dihydrate solution (5 mg of SnCl2.2H2O/1 ml of 0.01 M HCl) is added, the reaction mixture is put into an ultrasound bath for 5 minutes and finally incubated for 25 minutes at room temperature. The stent is dried and washed three times for 15 minutes with 2.5 ml of 0.9% sodium chloride solution. Finally, it is again covered with a layer of 2.5 ml of 0.9% sodium chloride solution, and the reaction mixture is put into an ultrasound bath for 5 minutes. The dried Wiktor stent carries an activity of 5.2 MBq-Re-186/22.31 mg (≅140.5 μCi/22.31 mg≅6.3 μCi/1 mg).
The Wiktor stent (model 6570, Medtronic) was coated with Tc-99m as described in Example 10. In an anesthetized (Rompun/Ketavet 1:2) white New Zealand rabbit (3.2 kg of body weight), the femoral artery was exposed. The labeled Wiktor stent was inserted into the vessel via a 5 F sluice and secured in the infrarenal aorta by inflating the balloon catheter. The catheter was then removed, and both the femoral artery and the wound were sutured. Over a period of 8 hours after administration of the stent, whole-body scintigrams were prepared with the aid of a commercially available gamma camera. Figure XI shows a scintigram that was prepared five hours after administration of the stent. Activity could only be located in the area of the stent that is in the infrarenal aorta of the animal. During the entire examination period, no detectable activity was rinsed from the stent. After 8 hours, the rabbit was killed, the stent was removed, and the activity was measured in a gamma counter. The activity that adheres to the stent was equally as high as at the beginning of the test.
A Strecker stent (about 200 mg) is coated with gold (2 minutes of 30 mg of gold(III)-chloride in 30 ml of 5% aqueous solution) in a cementation vessel (
500 mg of 11-aminoundecyl-1-thiol is dissolved in a solution that consists of 10 ml of 7.5% aqueous nitric acid/5 ml of tetrahydrofuran/3 ml of 1,2-dichloromethane. The Strecker stent that is produced from Example 26a is immersed in this solution under protective gas (in an ultrasound bath/37° C.). It is irradiated for about 15 minutes. The stent is washed three times with ethanol, then twice with acetonitrile.
The stent that is described in Example 26b is immersed in a 7.5% aqueous sodium carbonate solution, and 500 mg of DTPA-bis-anhydride in 5 portions per 100 mg each is added at 0° C. while being stirred. It is stirred for 10 minutes at 0° C. The stent is washed twice with 5% aqueous hydrochloric acid, then three times with water and twice with acetonitrile.
The stent that is described in Example 26c is immersed in a solution of acetate buffer (0.001 mol, pH 5.5), and In-111 solution (starting activity: 48.8 MBq) is added. It is stirred for 5 minutes at room temperature. The stent is washed three times with 3% aqueous sodium carbonate solution, then twice with physiological common salt solution. The stent can be used directly for implantation. The stent showed a radioactivity of 1.2 MBq.
The stent that is obtained from Example 26b is immersed in a solution of phosphate buffer (0.1 mol/l, pH 7.4), and 150 mg of 1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA) is added. It is cooled to 0° C., and 200 mg of N-hydroxysulfosuccinimide (Sulfo-NHS) and 200 mg of 1-ethyl-3-(dimethylaminopropyl)-carbodiimide HCl (EDC) are added. It is stirred for 30 minutes at 0° C. The stent is washed twice with water and twice with physiological common salt solution.
The stent that is described in Example 27a is immersed in a solution of acetate buffer (0.01 mol, pH 5), and In-111 solution (starting activity: 37.3 MBq) is added. It is heated for 30 minutes to 50° C. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological common salt solution. The stent showed a radioactivity of 1.45 MBq.
A stent that is prepared in Example 26b is immersed in a solution of sodium carbonate buffer (0.1 mol/l, pH 9), and 100 mg of 4-isothiocyanato-benzyl-DTPA (Gansow, O. WO 91/14459) is added. It is stirred for 30 minutes at room temperature. The stent is washed twice with 3% sodium carbonate solution, then three times with physiological common salt solution.
The stent that is described in Example 28a is immersed in a solution of acetate buffer (0.01 mol, pH 5), and Cu-67 solution (starting activity: 34.5 MBq) is added. It is stirred for 5 minutes at room temperature. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological common salt solution. The stent showed a radioactivity of 0.98 MBq.
A stent that is prepared in Example 26b is immersed in a solution of sodium carbonate buffer (0.1 mol/l, pH 9), and 100 mg of 4-isothiocyanato-benzyl-DOTA (Gansow, O. U.S. Pat. No. 4,923,985) is added. It is stirred for 30 minutes at room temperature. The stent is washed twice with 3% sodium carbonate solution, then three times with physiological common salt solution.
The stent that is described in Example 29a is immersed in a solution of acetate buffer (0.01 mol, pH 5), and Cu-67 solution (starting activity: 28.6 MBq) is added. It is stirred for 15 minutes at 40° C. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological common salt solution. The stent showed a radioactivity of 0.77 MBq.
10 g (28 mmol) of DTPA-bis-anhydride is suspended in 100 ml of dimethyl sulfoxide. It is cooled to 0° C., and 5.7 g (56 mmol) of triethylamine is added. Then, 1.58 g (7 mmol) of cystamine dihydrochloride is added, and it is stirred for 24 hours at room temperature. 20 ml of formic acid and 1000 ml of diethyl ether are added. The precipitated solid is filtered off and chromatographed on RP18 (mobile solvent: gradient that consists of acetonitrile/THF/water). Th product that is obtained after the main fractions are concentrated by evaporation is recrystallized from a little methanol.
The Strecker stent that is described in Example 26a is fixed in an electrolysis cell (
The stent that is described in Example 30b is immersed in a solution of acetate buffer (0.01 mol, pH 5), and In-111 solution (starting activity: 34.7 MBq) is added. It is stirred for 5 minutes at room temperature. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological common salt solution. The stent showed a radioactivity of 1.11 MBq.
The stent that is described in Example 30b is immersed in a solution of acetate buffer (0.01 mol, pH 5), and Cu-67 solution (starting activity: 41.2 MBq) is added. It is stirred for 3 minutes at room temperature. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological common salt solution. The stent showed a radioactivity of 0.97 MBq.
The Strecker stent that is described in Example 26a is fixed in an electrolysis cell (
The stent that is described in Example 32a is immersed in a solution that consists of 30 ml of acetate buffer (0.01 mol, pH 5 and 100 mg of tin(II)-chloride), and Re-186 solution (starting activity: 48.3 MBq) is added. It is stirred for 3 minutes at room temperature. The stent is washed twice with 3% aqueous sodium carbonate solution, then three times with physiological common salt solution. The stent showed a radioactivity of 1.44 MBq.
The Strecker stent that is described in Example 26a is fixed in an electrolysis cell (
The Strecker stent that is described in Example 26a is fixed in an electrolysis cell (
A stent that is produced according to 26a is put into a solution that consists of 5% aqueous hydrochloric acid, and a solution of S-35-cysteine (initial activity 37.5 MBq) is added. It is stirred for 5 minutes at room temperature. The stent is washed four times with physiological common salt solution. A radioactivity of 1.35 MBq is measured.
A Strecker stent (93 mg) is fixed in an electrolysis cell as described in
A nitinol stent (about 500 mg) was labeled analogously as described in Example 1. Electrolysis is done for 10 minutes at 1.5 V, however. The stent showed a radioactivity of 3.21 MBq.
A nitinol stent (about 1000 mg) is fixed in an electrolysis cell as described in
A Palmaz stent (about 200 mg) is fixed in an electrolysis cell (
A Strecker stent (about 150 mg) is in an electrolysis cell (
A Strecker stent (about 350 mg) is in an electrolysis cell (
A Z-stent (about 250 mg) is in an electrolysis cell (
A Z-stent (about 250 mg) is in an electrolysis cell (
A nitinol stent (about 1500 mg) is in an electrolysis cell (
A nitinol stent (about 1500 mg) is in an electrolysis cell (
A Z-stent (about 500 mg) is in an electrolysis cell (
In a cementation vessel (
In a cementation vessel (
In a cementation vessel (
In a cementation vessel (
A Strecker stent is brought into an electrolysis cell (
A Strecker stent is brought into an electrolysis cell (
In a cementation vessel (
In a cementation vessel (
A Palmaz stent is brought into an electrolysis cell (
In a cementation vessel (
A Palmaz stent (15 mm, 80.3 mg, Johnson and Johnson) is covered with a layer of 1.0 ml of labeling solution that consists of 173 μl of sodium perrhenate solution (164 MBq) and 827 μl of 1N HCl. The reaction vessel is placed in an ultrasound bath (80% US power) for 60 minutes at 50° C. Then, the stent is removed, rinsed with distilled H2O and dried. The dried stent carries an activity of 36.2 MBq=0.45 MBq/mg of stent. To remove non-specifically-bonded activity, the stent is incubated for 60 minutes in 1 ml of 0.9% NaCl solution at 37° C. After drying, the stent still carries an activity of 9.7 MBq=0.12 MBq/mg of stent.
A Palmatz stent (1/11 stent=26.2 mg, Johnson & Johnson) is covered with a layer of 1.5 ml of labeling solution that consists of 60 μl of perrhenate solution (60 MBq) and 1440 μl of IN HCl. The reaction vessel is tightly sealed and heated for 30 minutes to 100° C. (boiling water bath). Then, the stent is removed, rinsed with distilled H2O and dried. The dried stent carries an activity of 25.9 MBq (0.98 MBq/mg of stent). To remove or fix non-specifically-bonded activity, the stent is incubated for 10 minutes in 2 ml of 0.1 M gentisic acid/0.1 M SnCl2 solution while being shaken. After drying, the stent carries an activity of 16.1 MBq (0.61 MBq/mg of stent).
A Palmatz stent (31.4 mg, Johnson & Johnson) is covered with a layer of 1.5 ml of labeling solution that consists of 60 μl of sodium perrhenate solution (81 MBq) and 1440 μl of 0.75 N HCl. The reaction vessel is tightly sealed and heated for 30 minutes to 100° C. (boiling water bath). Then, the stent is removed, rinsed with distilled H2O and dried. 27.1 MBq (0.86 MBq/mg of stent) is fixed on the dried stent. To remove non-specifically-bonded activity, the stent is then incubated in 2 ml of 0.1 M alcoholic tetrabutylammonium bromide solution for 10 minutes while being shaken. After drying, 17.0 MBq (0.54 MBq/mg of stent) is fixed on the stent.
After drying at room temperature several times, the stent of Example 59 is immersed in a solution that consists of 16% vinyl acetate-acrylate polymer in ethyl acetate. After drying, the stent is ready for use.
Addition of solutions: Hypodermic syringes or metering pumps When addition is done with hypodermic syringes: Put septa in the cover.
If electrolysis is carried out at an elevated temperature, the solution is preheated.
| Number | Date | Country | Kind |
|---|---|---|---|
| 197 18 342.5 | Apr 1997 | DE | national |
| 197 18 341.7 | Apr 1997 | DE | national |
| 197 18 340.9 | Apr 1997 | DE | national |
| 197 24 223.5 | Jun 1997 | DE | national |
| 197 24 229.4 | Jun 1997 | DE | national |
| 197 24 230.8 | Jun 1997 | DE | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09627321 | Jul 2000 | US |
| Child | 10718580 | Nov 2003 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09403924 | US | |
| Child | 09627321 | Jul 2000 | US |
